Benzo[a]pyrene affects development and function of human GnRH neuroblasts

The increasing environmental pollution represents a major con- cern not only for the global ecosystem, but also for human health. Endocrine disrupting chemicals (EDCs), such as benzo[a]pyrene (BaP), are widespread pollutants that can inter- fere with the endocrine system, altering reproductive function and embryo development. However, little is known about BaP effects on human reproductive axis at central level. The central regulatory network of the reproductive system is mediated by gonadotropin-releasing hormone (GnRH) neurons, which origi- nate in the olfactory placode and, during fetal development, migrate into the hypothalamus.We investigated the direct effects of BaP on development of GnRH-secreting neurons taking advantage of a primary culture isolated from the human fetal hypothalamus (hfHypo). hfHypo cells express the enzymes cytochrome P450 (CYP1A1 and 1B1), required for metabolic activation of BaP and that expression was strongly induced by Bap exposure (0.2 and 10 μM for 24 h). Moreover, treating hfHypo with BaP (10 μM, 24 h) increased reactive oxygen species (ROS) production and influenced the total antioxidant capacity of the cells. From a functional point of view, BaP expo- sure (10 μM, 24 h) significantly reduced both mRNA and protein expression of GnRH and decreased the mRNA level of the recep- tor for kisspeptin (KISS1R), the main physiological regulator of GnRH neuron function. In addition, since the migratory process is a crucial event for the correct maturation and functionality of GnRH neurons, we investigated the effect of BaP on pre-migra- tory GnRH neuroblasts isolated from the human fetal olfactory epithelium (FNC-B4). Preliminary results, using a transwell assay, indicated that BaP pre-incubation (10 μM for 24 h) sig- nificantly reduced FNC-B4 migratory properties. In conclusion, our findings demonstrate that BaP may directly affect GnRH neuron maturation and function by altering migration process and interfering with GnRH and KISS1R expression, suggesting a possible mechanism underlying EDCs-related alterations of reproductive function.